1. Technical Field of the Invention
The present invention relates to novel N-phenylacetamide compound inhibitors of the enzyme SOAT-1 (Sterol-O-Acyl Transferase-1), likewise named ACAT-1 (Acylcoenzyme A Cholesterol Acyl Transferase). It also relates to their formulation into pharmaceutical compositions useful in human or veterinary medicine, or else into cosmetic compositions and, likewise, their non-therapeutic applications.
2. Description of Background and/or Related and/or Prior Art
The compounds having an activity of the type inhibiting SOAT-1 are widely described in the literature as having activities in the regulation of biological processes involving cholesterol and its derivatives. These properties confer to this class of compounds a great potential in the treatment or the prevention of numerous pathologies, and more particularly in dermatology and in cardiovascular diseases or complaints of the central nervous system. The majority of the biological effects of the inhibitors of SOAT-1 are mediated by the prevention of the synthesis of esters of cholesterol by the enzyme SOAT-1. Among the documents of the prior art describing molecules inhibiting SOAT-1, exemplary are WO 96/10559, EP-0370740, EP-0424194, U.S. Pat. No. 4,623,663, EP-0557171, U.S. Pat. No. 5,003,106, EP-0293880, EP-0433662 and U.S. Pat. No. 5,106,873, which describe compounds for treating arteriosclerosis or hypercholesterolaemia to be treated. The therapeutic potential of inhibitors of SOAT-1 in the treatment of cardiovascular diseases and, in particular, of hypercholesterolaemia and of arteriosclerosis is likewise described by Kharbanda R. K. et al., in Circulation, 2005, 11, 804. The potential of inhibitors of SOAT-1 for the treatment of Alzheimer's disease has likewise been reported in the literature, for example, by Puglielli, L. et al., in Nature Neurosciences 2003, 6 (4), 345.
U.S. Pat. Nos. 6,133,326, 6,271,268 and WO 2005/034931 describe compounds which are inhibitors of SOAT-1 for inhibiting the production of sebum. In the field of dermatology in particular, it is particularly advantageous to prevent the excessive production of sebum and all the associated conditions. Sebum is produced by the sebaceous gland. The greater concentration of sebaceous glands is situated on the face, the shoulders, the back and the scalp. The sebum is secreted on the surface of the skin, where it plays a major physiological role, associated with the maintenance of the cutaneous barrier and of a microenvironment allowing the regulation of the bacterial flora and cutaneous fungus.
The hyperproduction of sebum is, most often, associated with a skin or a scalp of greasy appearance, a cause of discomfort and a degraded appearance. In addition, the hyperproduction of sebum can breed seborrhoeic dermatitis and is associated with an increased incidence or severity of acne. The esters of cholesterol produced in the sebaceous gland by SOAT-1 are one of the components of sebum, among several classes of lipids including the triglycerides, the esters of waxes and the squalenes, as described by Nikkari, T., in J Invest Derm 1974, 62, 257. The inhibition of this enzyme or other acyltransferases can thus allow the production of sebum to be inhibited. U.S. Pat. No. 6,133,326 describes, in particular, the inhibition of the sebum by inhibitors of ACAT-1 (likewise named SOAT-1). Nevertheless, to date, no treatment utilizing such inhibitors is available commercially. The only treatments for the disorders linked to hyperseborrhoea to be remedied or relieved are systemic hormonal treatments or systemic treatment with 13-cis-retinoic acid, treatments whose secondary effects considerably limit their field of application. There thus exists a clear cosmetic and medical need for the treatment of disorders and pathologies linked to the hyperproduction of sebum.